Diabetic complications can be reduced by normalization of blood glucose levels via intensive insulin therapy. This treatment, while effective, bears the risk of an increased incidence of recurrent hypoglycemia. It blunts the central counterregulatory response to low blood glucose (counterregulatory failure) and thereby magnifies the risk of severe hypoglycemia and brain injury. The overall goal of this proposal is to understand the changes in brain metabolism that underlie these phenomena and identify possible therapies in order to prevent them. We will determine the impact of a medium chain fatty acid enriched diet on brain metabolism in tightly controlled T1DM subjects with hypoglycemia unawareness and an animal model thereof. We will further test the hypothesis that chronic provision of medium chain fatty acids can improve cognitive performance under hypoglycemia in human subjects. Data gathered from our animal studies revealed a specific change of neuronal energy metabolism under hypoglycemia following exposure to antecedent recurrent hypoglycemia that make is more difficult for neurons to utilize fuels like glucose or lactate. We also found that after recurrent hypoglycemia, lactate uptake into the brain was facilitated, but because it could subsequently not be utilized by mitochondria as effectively as under control conditions, it may not be an ideal fuel. This let us to look for different alternate substrates that follow the same route of uptake as lactate, but enter metabolism via a different pathway. One group of fuels that fulfill these criteria are ketone bodies and medium chain fatty acids. Applying state of the art technologies like in vivo NMR spectroscopy to our animal model of recurrent hypoglycemia will allows us address the hypothesis that they are better suited to support metabolism. We will use this animal model to determine how diabetes confounds the adaptations induced by recurrent hypoglycemia alone and then go on to translate our findings to a clinical study of cognition and metabolism in intensively treated T1DM patients. Our work is the first step towards developing candidate molecules into novel therapies that would protect the brain from hypoglycemia induced brain injury. The projects proposed here are building on preliminary studies that I have performed during my NRSA fellowship training and since then. They will give me the ideal opportunity to continue my training in NMR spectroscopy and its application to neuroscience and diabetes related complications. Most of my training thus far has been in the use of basic science methods and animal models. Wanting to become a well trained physician scientist however I realized that I still needed more training in human investigation. To that end I enrolled in a Master of Health Sciences program to receive further training in translational methods. Funding under this career award will allow me to continue these activities and give me the protected time from clinical duties that I will need to accomplish my career goal of establishing myself as an independently funded physician-scientist, eventually with my own laboratory and workgroup. PUBLIC HEALTH RELEVANCE: Understanding the changes of brain energy substrate transport and metabolism in intensively treated type 1 diabetic patients will provide the basis for the identification of novel therapeutic approaches that could protect the brain from hypoglycemia induced injury. This in turn could then sustain normal brain metabolism under hypoglycemia and would also allow for tighter glucose control with better protection from long-term diabetic related complications.